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Synthetic Retinoid Sulfarotene Selectively Inhibits Tumor-Repopulating Cells of Intrahepatic Cholangiocarcinoma via
Xiaojing Du1,2, Zhuoran Qi1, Sinuo Chen1
1Liver Cancer Institute, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai, 200032, China.
Abstract:
Intrahepatic cholangiocarcinoma (ICC) is a highly lethal malignancy that currently lacks effective clinical treatments. Eliminating stem cell-like cancer cells is an extremely promising but challenging strategy for treating ICC. A recently developed synthetic retinoid, sulfarotene, abrogates proliferation, and induces apoptosis of tumor-repopulating cells (TRCs) that exhibit stem cell-like properties, yet its effect and underlying mechanisms remain elusive in ICC. It is found that although 5-fluorouracil, cisplatin, pemigatinib, and gemcitabine all inhibit ICC-TRCs, sulfarotene demonstrates superior efficacy. Sulfarotene induces retinoic acid receptor alpha (RARɑ) translocation from the cytoplasm to the nucleus, suppressing P-selectin expression at the transcriptional level. Moreover, it directly interacts with fucosyltransferase 8 (FUT8), inhibiting the core fucosylation of P-selectin glycoprotein ligand 1 (PSGL1). These actions collectively inhibit ICC-TRCs via destroying PSGL1-regulated cytoskeleton. The findings provide a strategy of inhibiting P-selectin/PSGL1 interaction and altering PSGL1 glycosylation pattern to compromise the cytoskeletal integrity and eliminate ICC-TRCs.
Insights
Sulfarotene effectively eliminates stem cell-like cancer cells in intrahepatic cholangiocarcinoma (ICC) by targeting P-selectin/PSGL1 interactions. This novel approach offers a promising strategy for treating this lethal malignancy.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- Intrahepatic cholangiocarcinoma (ICC) is a lethal cancer with limited treatment options.
- Targeting cancer stem cell-like properties is a promising therapeutic strategy for ICC.
- The efficacy and mechanisms of sulfarotene against ICC stem cells are not well understood.
Purpose of the Study:
- To investigate the efficacy of sulfarotene in eliminating ICC tumor-repopulating cells (TRCs).
- To elucidate the underlying molecular mechanisms of sulfarotene's action in ICC.
Main Methods:
- Comparison of sulfarotene with standard ICC chemotherapies (5-fluorouracil, cisplatin, pemigatinib, gemcitabine) against ICC-TRCs.
- Analysis of sulfarotene-induced retinoic acid receptor alpha (RARɑ) translocation.
- Investigation of sulfarotene's interaction with fucosyltransferase 8 (FUT8) and its effect on P-selectin glycoprotein ligand 1 (PSGL1) core fucosylation.
- Assessment of PSGL1-regulated cytoskeleton integrity.
Main Results:
- Sulfarotene demonstrated superior efficacy in inhibiting ICC-TRCs compared to other tested agents.
- Sulfarotene induced RARɑ translocation to the nucleus and suppressed P-selectin expression.
- Sulfarotene directly interacted with FUT8, inhibiting PSGL1 core fucosylation and disrupting the PSGL1-regulated cytoskeleton.
Conclusions:
- Sulfarotene effectively eliminates ICC-TRCs by targeting P-selectin/PSGL1 signaling and PSGL1 glycosylation.
- This study provides a novel therapeutic strategy for ICC by disrupting cytoskeletal integrity via P-selectin/PSGL1 inhibition.
- Targeting P-selectin/PSGL1 interactions and altering PSGL1 glycosylation presents a promising avenue for ICC treatment.
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